Molecular pathogenesis of hematologic malignanciesAcute Lymphoblastic Leukemia: Monitoring Minimal Residual Disease as a Therapeutic Principle
Section snippets
Analysis of Immunoglobulin and Polymerase Chain Reaction T-Cell Receptor Gene Rearrangements
During early B- and T-cell development, immunoglobulin (Ig) and T-cell receptor (TCR) genes are rearranged by the assembly of variable (V), diversity (D), and joining (J) elements into V(D)J segments encoding the variable regions of both antibodies and TCRs through a process called V(D)J recombination. The resulting junctional regions are specific for the individual cells and its descendants with the level of specificity depending on the number of V, D, and J elements in the germline and the
Prognostic Significance of MRD During Front-line Therapy
The most significant application of MRD for the treatment of de novo ALL is the refinement of initial risk stratification, because several large studies in childhood ALL as well as in adult ALL have shown that the initial MRD kinetics is highly predictive for outcome.5, 6, 12, 22, 25, 26, 27, 36, 37, 46, 65, 68, 81, 82 MRD negativity after induction as measured with a sensitivity of at least 10−4 was shown to be associated with only a 3% (v 39% in the MRD-positive group) relapse rate at 3 years
Methodological Aspects of MRD Assessment Within Clinical Trials
Assessment of MRD has been shown to be feasible even within large multicenter trials. Of the 2,143 patients with B-lineage ALL enrolled on 9900 series treatment protocols of the Children's Oncology Group, in 92% of patients day 29 samples were studied for MRD by flow cytometry at a sensitivity of at least 10−4.24
The AIEOP-BFM ALL 2000 trial used Ig/TCR-based RQ-PCR for MRD assessment in 3,341 patients: 2,365 (71%) patients had two or more sensitive targets (10−4), 671 (20%) patients revealed
MRD as Tool for Treatment Tailoring
There are various ways to use MRD information for tailoring treatment. Most study groups use MRD as tool for risk-group classification during front-line therapy. In childhood ALL, the AIEOP-BFM study group defined three risk groups according to MRD at day 33 and day 78 within their AIOP-BFM ALL 2000 protocol, with randomized treatment de-escalation for MRD–low-risk (LR) patients, treatment intensification for MRD–high-risk (HR) patients, and randomized treatment intensification for
Conclusion
MRD has proven to be an independent prognostic factor in childhood an adult ALL. Quantitative PCR and flow cytometry are currently the most widely used techniques for MRD quantification, each with specific advantages and disadvantages that have to be weighed carefully. In addition, precise MRD levels and optimal sampling time-points have to be defined for each treatment protocol before MRD-based risk stratification can be implemented. Whether or not outcome of patients can be improved by
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Cited by (64)
Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia
2021, Blood AdvancesCitation Excerpt :Among patients who relapsed following CAR-T, 85% had detectable NGS MRD in the PB post–CAR T, with median time from first MRD+ result post–CAR T to clinical relapse of 60 days (IQR, 50-139). Assessment of MRD is an essential component of ALL management.2,9,10 Adult ALL routinely undergo MRD evaluations from BM; patients with detectable MRD may undergo frequent repeat BM evaluations, whereas those who achieve MRD− status are often monitored via routine blood counts and clinical history.
Differential expression of CD73, CD86 and CD304 in normal vs. leukemic B-cell precursors and their utility as stable minimal residual disease markers in childhood B-cell precursor acute lymphoblastic leukemia
2019, Journal of Immunological MethodsCitation Excerpt :In order to further investigate the potential utility of the three markers evaluated here for MRD monitoring, we assessed their stability together with other frequently used MRD markers such as CD34, CD10 and CD20 during the early phases of therapy (i.e., day +15 of therapy). As previously shown (Basso et al., 2009; Brüggemann et al., 2012; Campana, 2012; Kusenda et al., 2014; Pieters and Carroll, 2008), MRD-positivity levels >0.1% are frequently observed at this time in the majority of patients, which ensures more reliable comparative analyses than at later time points with lower levels and lower rates of MRD-positivity. Of the three markers evaluated, CD73 turned out to be the most stable, being expressed at equal or higher levels in virtually all (95%) cases, without complete loss of CD73 expression being observed among our cases.
SOHO State of the Art Update and Next Questions: Advances in the Treatment of Adult Acute Lymphoblastic Leukemia
2019, Clinical Lymphoma, Myeloma and Leukemia
Conflict-of-Interest Disclosure: The authors declare no competing financial interests.